Method for treating obesity

ABSTRACT

The present invention relates, in general, to obesity, and, in particular, to a method of treating obesity and minimizing metabolic risk factors associated therewith using, for example, zonisamide or other weight-loss promoting anticonvulsant either alone or in combination with bupropion or other compound that enhances the activity of norepinephrine and/or dopamine via uptake inhibition or other mechanism.

This application claims priority from Prov. Appln. No. 60/380,874, filedMay 17, 2002, the content of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates, in general, to obesity, and, inparticular, to a method of treating obesity and minimizing metabolicrisk factors associated therewith using, for example, zonisamide orother weight-loss promoting anticonvulsant either alone or incombination with bupropion or other compound that enhances the activityof norepinephrine and/or dopamine via uptake inhibition or othermechanism.

BACKGROUND

The prevalence of obesity has risen significantly in the past decade inthe United States and many other developed countries, (Fiegal et al,Int. J. Obesity 22:39-47 (1998), Mokdad et al, JAMA 282:1519-1522(1999)). Because obesity is associated with a significantly elevatedrisk for type 2 diabetes, coronary heart disease, hypertension, andnumerous other major illnesses, and overall mortality from all causes(Must et al, JAMA 282:1523-15219 (1999), Calle et al, N. Engl. J. Med.341:1097-1105 (1999)), weight reduction is critical for the obesepatient (Blackburn, Am. J. Clin. Nujtr. 69:347-349 (1999), Galuska etal, JAMA 282:1576 (1999)). There is good evidence that pharmacotherapycan enhance weight loss when combined with interventions aimed atchanging life style (National Heart, Lung and Blood Institute, Clinicalguidelines on the identification, evaluation, and treatment ofoverweight and obesity in adults: the evidence report, NIH PublicationNo. 98-4083, September 1998). Yet, the available pharmacologicaltherapies to facilitate weight loss fail to provide adequate benefit tomany obese patients because of side effects, contraindications or lackof positive response (National Heart, Lung and Blood Institute, Clinicalguidelines on the identification, evaluation, and treatment ofoverweight and obesity in adults: the evidence report, NIH PublicationNo. 98-4083, September. 1998). Hence, there is impetus for developingnew and alternative treatments for management of obesity.

Zonisamide (ZONEGRAN®) is a marketed antiepileptic drug (AED). Inshort-term clinical trials of zonisamide in epileptic patients takingother concomitant AEDs, a small degree of weight loss was observed as anadverse effect in a small percent of patients (Oommen and Matthews,Clin. Neuropharmacol. 22:192-200 (1999)). The anticonvulsant activity ofzonisamide is believed to be related to its sodium and calcium channel(T-type) channel blocking activity (Oommen and Matthews, Clin.Neuropharmacol. 22:192-200 (1999)). This drug is also known to exertdopaminergic (Okada et al, Epilepsy Res. 22:193-205 (1995)) as well asdose-dependent biphasic serotonergic activity (Okada et al, EpilepsyRes. 34:187-197 (1999)).

Topiramate (TOPAMAX®) is an AED that has been demonstrated in clinicaltrials of human epilepsy to be effective as adjunctive therapy intreating simple and complex partial seizures and secondarily generalizedseizures (Faught et al, Epilepsia 36(S4):33 (1995); Sachdeo et al,Epilepsia 36(S4):33 (1995)). It is currently marketed as adjunctivetherapy for partial onset seizures or primary generalized tonic-clonicseizures.

Bupropion, marketed as an antidepressant, has a pharmacological actiondissimilar to that of zonisamide or topiramate. Bupropion has been shownto cause significant weight loss in patients presenting with primaryobesity (Gadde et al, Obes. Res. 9(9):544 (2001)).

The present invention results, at least in part, from studiesdemonstrating that zonisamide is more effective than placebo for weightloss in obese subjects. The use of zonisamide (or other weight-losspromoting anticonvulsant) and bupropion (or other compound that enhancesmonoamine (e.g., serotonin, norepinephrine and/or dopamine) turnover inthe brain via uptake inhibition or other mechanism) provides aneffective treatment for obesity with few side effects.

SUMMARY OF THE INVENTION

The present invention relates generally to obesity. More specifically,the invention relates to a method of treating obesity and minimizingmetabolic risk factors associated therewith using, for example,zonisamide or other weight loss-promoting anti-convulsant either aloneor in combination with bupropion or other compound that enhances theactivity of norepinephrine and/or dopamine via uptake inhibition orother mechanism.

Objects and advantages of the present invention will be clear from thedescription that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Disposition of study subjects.

FIG. 2. Pattern of weight change from baseline to Week 16 in obesesubjects who received zonisamide (n=30) or placebo (n=30). Resultsplotted as means (SE). Data are from the lastobservation-carried-forward (LOCF) analysis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating obesity in ananimal. The invention further relates to a method of minimizingmetabolic risk factors associated with obesity, such as hypertension,diabetes and dyslipidaemia. In one embodiment, the methods compriseadministering to an animal in need of such treatment an effective amountof zonisamide or other weight-loss promoting anticonvulsant. In analternative embodiment, the methods comprise administering a combinationof zonisamide or topiramate, or other weight-loss promotinganticonvulsant (including agents that block kainate/AMPA (D,L-α-amino-3-hydroxy-5-methyl-isoxazole propionic acid) subtype glutamatereceptors), and bupropion, or other compound that enhances the activityof norepinephrine and/or dopamine via uptake inhibition or othermechanism, in effective amounts.

Preferred active agents for use in the present invention includezonisamide or topiramate (and pharmaceutically acceptable saltsthereof), however, other methane-sulfonamide derivatives, such as thosedescribed in U.S. Pat. No. 4,172,896, or other sulfamates (includingsulfamate-substituted monosaccharides), such as those described in U.S.Pat. No. 4,513,006, can also be used. While the use of bupropion is alsopreferred, compounds disclosed in U.S. Pat. Nos. 3,819,706 and 3,885,046can be used, as can other compounds that enhance the activity ofnorepinephrine and/or dopamine via uptake inhibition or other mechanism(e.g., Atomoxetine or Reboxetine).

As used herein, the term “obesity” includes both excess body weight andexcess adipose tissue mass in an animal. An obese individual is one(e.g., 21-50 years old) having a body mass index of ≧30 kg/m². While theanimal is typically a human, the invention encompasses the treatment ofnon-human mammals.

The amount of active agent(s) (e.g., zonisamide alone or in combinationwith, for example, bupropion) administered can vary with the patient,the route of administration and the result sought. Optimum dosingregimens for particular patients can be readily determined by oneskilled in the art.

When zonisamide is used alone, the dose can be from about 25 mg to about800 mg per day, generally given once per day or divided (e.g., equally)into multiple doses. Preferably, the dose is from about 100 mg to about600 mg per day, more preferably, the dose is from about 200 mg to about400 mg per day. However, it may be necessary to use dosages outsidethese ranges.

When the combination therapy is used, the daily dose of, for example,zonisamide can be from about 25 mg to about 800 mg, preferably fromabout 100 mg to about 600 mg, more preferably from about 200 mg to about400 mg. When topiramate is used in combination therapy, the daily doseof topiramate can be from about 25 mg to about 1600 mg, preferably fromabout 50 mg to about 600 mg, more preferably from about 10 mg to about400 mg. The daily dose of bupropion used can be from about 25 mg toabout 60 mg, preferably from about 50 mg or about 150 mg to about 450mg. The doses can be given once per day or divided (e.g., equally) intomultiple doses. It may be necessary to use dosages outside these ranges.When the combination therapy is used, the ratio of zonisamide (ortopiramate) to bupropion can range, for example, from about 2:1 to about1:2.

When the combination therapy is used, the individual components of thecombination can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms.

In accordance with the present invention, the active agent(s) (e.g.,zonisamide alone or in combination with bupropion) can be administeredin any convenient manner, such as orally, sublingually, rectally,parentally (including subcutaneously, intrathecharly, intramuscularlyand intravenously), or transdermally. The most preferred route ofadministration is the oral route.

The active agents of the invention can be administered in the form of apharmaceutical composition or compositions that contain one or both inan admixture with a pharmaceutical carrier. The pharmaceuticalcomposition can be in dosage unit form such as tablet, capsule, sprinklecapsule, granule, powder, syrup, suppository, injection or the like.Sustained released formulations can also be used. The composition canalso be present in a transdermal delivery system, e.g., a skin patch.

Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and4,172,896, as well as in patents cited therein.

In accordance with the invention, the combination of, for example,zonisamide or topiramate and bupropion (including sustained releasepreparations) is an effective treatment for obesity and provides aneffective means of minimizing metabolic risks associated with obesity.The combination can be more effective than, for example, zonisamide ortopiramate treatment alone and with fewer side effects.Neuropharmacologically, all three major nerve transmitters that regulateappetite and weight, i.e., seratonin, norepinephrine and dopamine, aretargeted with the combination of, for example, bupropion and zonisamideor topiramate. Side effects of, for example, zonisamide or topiramate(such as somnolence, psychomotor slowing, cognitive impairment, fatigueand depression) can be offset by insomnia, activation, psychomotoragitation and antidepressant effects of, for example, bupropion. On theother hand, zonisamide or topiramate, for example, can reduce theseizure risk associated with, for example, bupropion. Lower doses ofboth types of medication can be used in the combination treatment,thereby further reducing the overall side effect burden.

Certain aspects of the invention are described in greater detail in thenon-limiting Examples that follow and in Gadde et al, JAMA 289:1820(2003). (See also U.S. Pat. Nos. 6,323,236, 6,071,537, 6,548,551,6,506,799 and 6,191,117.)

EXAMPLE 1 Experimental Details Subjects

Sixty-eight subjects were screened for participation and 60 subjectswere randomized.

Inclusion criteria were: male or female, aged 21-50 years, with bodymass index (BMI) of ≧30 kg/m².

Exclusion criteria were: obesity of a known endocrine origin, such ashypothyroidism and Cushing's syndrome; serious/unstable medical orpsychiatric illness; current major psychiatric disorder; current drug oralcohol abuse; history of or current kidney disease or renal calculi;significant liver disease; uncontrolled hypertension; current diabetesmellitus (DM), type 1 or 2 DM receiving pharmacotherapy; untreated oruncontrolled thyroid disease; weight loss or gain greater than fourkilograms in past three months; history of obesity surgery; current orrecent use of any weight loss medications, herbs, or supplements;current or recent use of drugs, herbs, or dietary supplements known tosignificantly affect body weight; concomitant medications thatsignificantly affect P450 3A4 hepatic microsomal enzymes;hypersensitivity to sulfonamides; women of child-bearing age notadhering to an acceptable form of contraception; pregnant orbreast-feeding women; and, subjects judged to be unable to followinstructions and study procedures.

Study Design

The study had two phases. The first was the acute phase—a 16-week,randomized, double blind, parallel-group comparison of zonisamide (ZON)and placebo (PBO). This was followed by an optional 16-week extensionphase. At the end of the acute phase, subjects wishing to continuefurther received the same treatment for an additional 16 weeks in asingle-blinded fashion.

Randomization, Medication Dosing and Dispensing

The subjects were randomized in a 1:1 ratio to receive zonisamide orplacebo capsules. Study medication was dispensed under blindedconditions through computer-based randomization. The randomization wasgenerated using a random number table with a block size of ten. Therewas no stratification by gender or other demographics. The studyinvestigators were blind to the “blocking” method used by the pharmacy.The treatment assignment codes were not available to the investigatorsuntil all subjects completed the acute phase, the data were entered, andthe database for this phase was locked, meaning that no further changescould be made to the data.

The study medication was dispensed in the form of capsules. Each capsulecontained either 100 milligrams zonisamide or placebo. The capsules weremade to look identical. The dose escalation was as follows: one capsule(zonisamide 100 mg or placebo) every evening for the first 2 weeks; twocapsules (zonisamide 200 mg or placebo) every evening during Weeks 3 and4; three capsules (zonisamide 300 mg or placebo) every evening duringWeeks 5 and 6; and, four capsules (zonisamide 400 mg or placebo) everyevening from Week 7 onward. At Week 12, the dose could be increasedfurther to six capsules (zonisamide 600 mg or placebo) every evening forsubjects who had not lost at least 5% of their initial body weight. If asubject preferred not to take all six capsules at one time, taking ahalf of the daily dose in the morning was an option. Based ontolerability, dose escalation could be withheld, or the dose might alsobe decreased. Medication compliance was overseen by recording the numberof tablets returned and comparing this number to the number of capsulesdispensed at each visit.

Diet and Lifestyle Counseling

Subjects in both treatment groups were instructed to follow anindividual diet that was 500 Kcal/day less than what they needed tomaintain their weight. The prescribed diet, based on eating a variety offoods from the Food Guide Pyramid, emphasized decreasing portions,eating more fruits and vegetables, and drinking 8 cups of water eachday. Increased physical activity was also encouraged for subjects inboth groups. Subjects were asked to record their dietary intakeincluding portion sizes in food diaries, which were provided to them. Aregistered dietician reviewed food diaries and provided counseling toall subjects. Subjects were encouraged to make healthy changes in theirdiets and physical activity that could be maintained after thecompletion of the study.

Visits and Measurements

Subjects were seen at weeks 0, 2, 4, 8, 12, and 16 in the acute phase,and every four weeks in the extension phase. During each visit, thefollowing assessments were performed: blood pressure, heart rate,weight, dietary compliance, medication accountability and tolerability,and adverse effects. Body weight was measured on a calibrated electronicscale to the nearest 0.1 kilogram. A registered dietitian reviewed fooddiaries and assessed dietary compliance. Adverse effects were gatheredvia spontaneous reporting by subjects as well as open-ended inquiries bythe clinicians. Reportable adverse effects were new symptoms orillnesses that emerged during treatment or those that had an increase inseverity compared with baseline.

In addition to the above, the subjects completed the Impact of Weight onQuality of Life (IWQOL) (Kolotin et al, Obesity Res. 3:49-56 (1995)) atbaseline, Week 8, and Week 16. The IWQOL is a self-report measure with74 items that assess the perceived effect of weight on quality of lifein the following domains (subscales)—health, social/interpersonal life,work, mobility, self-esteem, sexual life, activities of daily living,and eating (comfort with food). Improvement with treatment is reflectedby decreasing scores on all the subscales with the exception of theeating (comfort with food) subscale, which is expected to show lesscomfort around food with effective treatment. Body composition (fat andlean masses) and bone mineral density (BMD) were determined, at baselineand Week 32, by dual x-ray absorptiometry (DXA; Hologic 2000, Waltham,Mass.). All DXA measurements were gathered using the same equipment andtechniques. Subjects were instructed to fast for 8 hours and not todrink water or other beverages for at least 4 hours prior to DXAmeasurement.

Endpoints and Measures of Outcome

Body weight was the primary end point. Examined were the absolute changein weight, percent change in weight, and the number of subjects in eachgroup that achieved weight losses of 5% and 10%. Secondary outcomemeasures included heart rate, blood pressure, frequency of adverseeffects, fasting electrolytes and lipids, waist measurement, VAS-C,IWQOL, body composition and BMD.

Statistical Analysis

All randomized subjects were included in the primary analysis. Putativedifferences between subjects in the zonisamide group versus subjects inthe placebo arm were tested using Student's t-test for continuousvariables and Fisher's exact test for categorical covariates. Adichotomous proxy variable denoting attrition status was also testedbetween groups using Fisher's exact test. Two subjects that withdrewafter completing only the baseline interview were excluded fromsubsequent analyses.

Weight change during the study was assessed in terms of actual weightchange over the six study intervals using multivariable regressionmethodology, and as a dichotomous outcome of. ‘response,’ i.e., 5%weight loss at Week 16, and 5% and 10% weight loss at Week 32. The proxyvariables denoting response status were tested across treatmentconditions again using Fisher's exact test. Three multivariableregression analyses were conducted. In the first, body weight at eachtime point was modeled using a random effects growth curve model.Heuristically, the model fits a regression line for each subject usingavailable data points, thus maximizing use of actual data. For thesecond set of analyses, body weights were regressed as above withmissing observations carried forward from the last recorded weight basedon an intent-to-treat approach (LOCF). The final model was restricted tothe subset of respondents with no missing data (completers). All modelsincluded covariates for gender and BMI as well as proxy variablesdenoting treatment condition, time, and a term for the interaction oftreatment with time; age race, and percent body fat at baseline were notsignificantly associated with weight loss and, hence, excluded from theabove models.

Secondary analyses were conducted over three general areas of interest.In each case, analyses were based on 2×2 repeated measures ANOVAs thatincluded time, drug condition, and their interaction (time-by-drug). Theprimary interest in each instance was to determine if subjects in thezonisamide condition were differentially affected relative to controlsas operationally determined by testing the significance of the estimatedinteraction term. Tests in first area of interest focused on clinicalindicators including levels of creatinine, glucose, triglycerides, highand low density lipoproteins (all assessed at baseline and studyconclusion), waist measurements (baseline, Week 8 and Week 16), bloodpressure (systolic and diastolic), and heart rate. The second generalarea of sampled quality of life indicators including activities of dailyliving, appetite, esteem, health, interpersonal relations, mobility,sex, and work using the IWQOL Scale; repeated measurements were taken atbaseline, Week 8, and Week 16). The final set of secondary analysessampled hunger and appetite using the Visual Analogue Scale for Hungerand Food Cravings. Categories sampled included sweets, breads, salts,fats, meats, sodas, and overall hunger. Measurements were sampled atbaseline, Week 8, and Week 16.

The frequency of occurrence of individual adverse effect was testedacross drug conditions using Fisher's exact test.

Results Subject Characteristics and Disposition

Of the 68 subjects screened for participation, 8 were ineligible (FIG.1). Sixty subjects were randomized—0.30 to receive zonisamide (ZON) and30 placebo. (PBO). Nine subjects—6 in the PBO group and 3 in the ZONgroup—dropped out of the acute phase; thus, 51 of 60 subjects-completedthe first 16 weeks. The attributed reasons for premature disdontinuationwere: adverse events (ZON 1, PBO 2), lost to follow-up (ZON 1, PBO 2),consent withdrawn (ZON 0, PBO 2), and protocol violation (ZON 1, PBO 0).

With regard to characteristics of subjects at baseline (Table 1), therewere no significant differences between the treatment groups with thefollowing exceptions: with regard to gender distribution, there was amarginal difference (p=0.08) as all five men in the study wererandomized to ZON. Baseline BMI was slighter lower (p=0.07) in the ZONgroup.

TABLE 1 Baseline Characteristics of the Subjects Zonisamide PlaceboCharacteristic (n = 30) (n = 30) Age, yrs 37.5 (1.3) 36.4 (1.6) Sex, No.Men 5 0 Women 25 30 Race, No. Black 12 17 White 18 13 Weight, kg 98.2(2.5) 97.8 (2.6) BMI, kg/m² 35.4 (0.7) 37.2 (0.8) Body fat, % 40.8 (0.9)42.6 (0.8) Age, weight, BMI and body fat are presented as group means(SE). BMI denotes body mass index, defined as weight in kilogramsdivided by the square of height in meters.

Presented first are the results of the acute phase (initial 16-weektreatment), which was double-blind, and included all randomizedsubjects. Since the extension phase was optional and single-blind, allthe important results from this phase are presented separately.

Dose

The prescribed mean highest daily dose of zonisamide was 427 (29) mg,corresponding to 4.27 capsules, whereas the placebo group received 5.00capsules (corresponding to 500 mg).

Weight Loss Percent and Absolute Change in Weight

The curves for weight change as a percent weight loss over the 16-weekduration for zonisamide and placebo groups are shown in FIG. 2 forsubjects in the intent-to-treat (ITT) analysis with LOCF. The mean (SE)estimated weight loss for the zonisamide group (n=30) was 5.98% (0.82%)compared with 1.02% (0.40%) for the placebo group (n=30); time xtreatment interaction was significant (F_(1,58)=22.05; p<0.0001) For theITT-LOCF population, the absolute weight changed for the zonisamidegroup from 98.17 (2.5) kg at baseline to 92.28 (2.47) kg at Week 16whereas for the placebo group, the corresponding change was 97.75 (2.63)kg to 96.86 (2.78) kg (time x treatment: F_(1,58)=24.65; p<0.0001).Results from random coefficient regression analyses supporteddifferential weight loss for zonisamide-treated subjects. Regardless ofimputation procedure, the drug-by-time interaction differedsignificantly from zero in all models. For the likelihood imputed model,the estimated regression coefficient associated with the interactionterm predicted weight loss per week in excess of 0.3 kg over the courseof the study; complimentary values for the other two models were 0.29kg/wk using LOCF intent-to-treat imputation, and 0.21 kg/wk as estimatedfrom the model based only on complete-data subjects. Among the remainingcovariates, female gender was associated with significantly lower weightlevels, while higher BMI scores were associated with increasing weightlevels, again irrespective of model.

For the subset of subjects completing the 16-week acute phase, thedifference between treatment groups in the achieved weight loss overtime was again significant (F_(1,49)=20.07; p<0.0001) with the ZON grouplosing 6.61% (0.81%) weight compared with the placebo group losing 1.30%(0.49%).

Responders (≧5% and ≧10% Weight Loss)

In the ITT-LOCF population, 17 of 30 subjects (57%) in the ZON group and3 of 30 subjects (10%) in the PBO group achieved weight loss of ≧5%weight loss at Week 16 (Fisher's Exact; p<0.0003); 7/30 ZON subjects and0/30 PBO subjects achieved ≧10% weight loss at Week 16 (p<0.0053).

Other Efficacy Measures

Waist circumference decreased more in the zonisamide group over the 16weeks (103.5 [1.6] cm to 97.2 [1.8] cm vs. 103.2 [1.9] cm to 100.5 [2.0]cm; time x treatment: F_(1,49)=7.75; p<0.0008). Heart rate decreased byan average of approximately 2 beats/min in the overall sample (p<0.0007)although there was no difference between the groups. Systolic anddiastolic blood pressure readings did not change by four months.

Safety Measures

Subjects assigned to ZON reported, on average, 2.1 adverse effects (AEs)over the study period compared with 1.6 AEs for PBO (t=−1.56; p<0.125).Of the individual AEs, 10 subjects in the ZON group and 1 in the PBOgroup reported fatigue (Fisher's Exact; p<0.006); there were no otherAEs that were reported differently by the treatment groups. Serumcreatinine increased from 0.79 (0.03) mg/dL at baseline to 0.92 (0.03)mg/dL with zonisamide treatment while the change for PBO was 0.76 (0.02)mg/dL to 0.79 (0.02) mg/dL (F_(1,49)=14.82; p<0.0003).

Extension Phase Results

Of the 37 subjects (ZON 20, PBO 17) who entered the extension phase, 36completed Week 32. One subject in the ZON group withdrew prematurelyciting time constraints. Ten of 19 zonisamide subjects and none of theplacebo subjects lost ≧10% weight at Week 32 (p<0.0004). Zonisamidesubjects had a mean weight loss of 9.37% (1.64%) at Week 32 comparedwith 1.82% (0.73% for placebo subjects (F_(1,34)=13.02; p<0.0001). Withregard to absolute weight in kilograms, the change over the 32 weeks forthe ZON group was from 96.88 (3.01) kg to 87.64 (2.95) kg contrastingwith change in the placebo group from 96.39 (2.95) kg to 94.85 (3.38) kg(time x treatment: F_(1,34)=14.76; p<0.0001)

Waist circumference decreased more in the zonisamide group over the 32weeks (103.5 [2.0] cm to 93.6 [2.2] cm vs. 103.8 [2.4] cm to 100.5 [2.5]cm; time x treatment: F_(1,34)=8.38; p<0001). Both treatments led todecrease in systolic blood pressure; however, the decrease was greaterin the ZON group (129.1 [2.5] mmHg to 122.3 [1.8] mmHg vs. 128.2 [1.8]mmHg to 126.8 [1.81] mmHg; time x treatment: F_(1,34)=2.72; p<0.0047).Diastolic blood pressure decreased with ZON treatment, but not with PBO(82.5 [1.8] mmHg to 79.7 [1.2] mmHg vs. 82.5 [1.8] mmHg to 82.2 [1.1]mmHg; time x treatment: F_(1,34)=1.99; p<0.0403) Heart rate showed nosignificant change with either treatment.

Bone mineral density at lumbar vertebrae (L-BMD) did not change overtime in either group. Total bone mineral density showed a small, butstatistically significant (p<0.017) increase in both groups although notclinically significant; there was no difference between the groups inthis regard.

The following measures of the Impact of Weight on Quality of Life(IWQOL) scale improved more significantly in the zonisamide group overthe placebo group at Week 32: Health (p<0.0030), Work (p<0.0051),Mobility (p<0.0019), and Activities of Daily Living (P<0.0005).

Serum creatinine increased from 0.78 (0.03) mg/dL at baseline to 0.92(0.03) mg/dL with zonisamide treatment while the change for PBO was 0.75(0.02) mg/dL to 0.77 (0.02) mg/dL (F_(1,34)=11.01; p<0.0001). Noclinically significant changes in mean lipid values were observed witheither treatment although significant reductions were observed for somesubjects.

Conclusion

This randomized study demonstrated that zonisamide produced a robustweight loss effect when used as an adjunct to a standard, but low-keydietary and lifestyle intervention. The drug's superior effect overplacebo was demonstrated in the various analyses conducted for both theacute phase (first 16 weeks) as well as the extension phase. Thedifference in the weight loss efficacy between the active treatment andplacebo was evident by 4 weeks and the gap widened as the studyprogressed. Given the low-key adjunctive dietary and lifestyleintervention provided in this study, weight loss of 9.4% at 32 weeks canbe regarded a significant finding.

Reductions in certain risk factors associated with obesity were alsoobserved. Waist circumference decreased more significantly withzonisamide therapy compared with placebo treatment, likely related togreater degree of weight loss with active treatment. There was also ameaningful reduction in systolic blood pressure although the subjectswere not hypertensive at study entry. Improvements were also noted inmobility, general health, occupational functioning, activities of dailyliving, reflecting an overall improved quality of life. No significantchanges in mean lipid levels were observed although significantreductions were seen for some subjects.

Zonisamide was generally well tolerated. Fatigue was the only adverseeffect that occurred at a higher frequency than with placebo treatment.Although not observed frequently in this study, the following adverseeffects occurred frequently in the zonisamide epilepsy trials:dizziness, cognitive impairment, and somnolence. Zonisamide is asulfonamide; there is a potential for hypersensitivity reactions.Serious hematologic events have also been reported. The risk of kidneystones also needs recognition. For the duration of treatment in thisstudy (approximately 8 months), the rate of occurrence of kidney stoneswith zonisamide therapy is estimated to be 62.5 per 1000 patient-yearsof exposure. Consistent with data from epilepsy trials, an increase inserum creatinine was noted with zonisamide therapy, but not withplacebo. Whereas the increase (approximately 16% increase) wassignificant, there was no further increase in the extension phase; novalue exceeded the upper limit of normal range and there were noclinical events associated with the increase.

EXAMPLE 2

A 35 y.o. obese female (weight 271 lb, BMI 40 kg/m²), who failed tobenefit from numerous weight loss interventions, was started onbupropion 150 mg/day and the dose was increased after 5 days to 150 mgtwice a day. After one month of treatment, she lost 5 lbs, but regained3.4 lbs during the second month—thus managing a net weight loss of 1.6lbs after 2 months on bupropion. At this point, zonisamide was added tothe regimen at 100 mg/day and the dose was increased after 2 weeks to200 mg/day. After one month on the combination therapy, the patient hadlost 11 lbs and reported no side effects. No further information isavailable as the patient has relocated.

EXAMPLE 3

A 47 y.o obese female (weight 246 lb, BMI 41.4 kg/m²), who had notbenefited from various treatments, was started on zonisamide 100 mg/dayand the dose was increased gradually to 400 mg a day over the next 4weeks. After one month of treatment, she lost 4.6 lbs, but there was nofurther weight loss during the second month. At this point, zonisamidedose was increased to 600 mg a day; the patient achieved an additionalweight loss of 0.6 lb in the next month. Thus, after 3 months ofzonisamide therapy, the total weight loss with zonisamide therapy was5.2 lb. Zonisamide was continued at the same dose and bupropion SR wasstarted at 100 mg a day. After 10 days, the dose of bupropion wasincreased to 20.0 mg a day. One month later, the patient had lost 8.2lbs and reported no side effects. She reported that she felt “full”after eating small portions of food, and had more energy. She had lostover 35 lbs over ten months on the combination therapy with no sideeffects.

EXAMPLE 4

A 46 y.o. obese female received zonisamide in a clinical trial andachieved weight loss of 35.6 lb over 32 weeks. During the 5 weeksfollowing discontinuation of zonisamide, she gained 7.7 lb. Zonisamidewas restarted, but this intervention was unsuccessful in offsetting theregained weight; after 16 weeks of therapy at doses up to 400 mg/d, thepatient gained 1.2 lb. At this point, bupropion was added at 150 mg/d.After 14 weeks of combined therapy, the patient lost 9.4 lb with noadverse effects.

All documents cited above are hereby incorporated in their entirety byreference.

1-17. (canceled)
 18. A method of promoting weight loss in a mammalcomprising: identifying a mammal in need of such weight loss; andadministering to said mammal at least one compound that enhances theactivity of norepinephrine and/or dopamine selected from the groupconsisting of bupropion, atomoxetine, and reboxetine, and at least oneweight-loss promoting anticonvulsant wherein said anticonvulsant is offormula (III):

wherein R₁ is hydrogen or a halogen atom, R₂ and R₃ are the same ordifferent and are each hydrogen or an alkyl having 1 to 3 carbon atoms,and one of X and Y is a carbon atom and another is a nitrogen atom,provided that the group —CH₂SO₂NR₂R₃ is bonded to the carbon atom ofeither of X and Y, or an alkali metal salt thereof.
 19. The method ofclaim 18, wherein said anticonvulsant is zonisamide.
 20. The method ofclaim 18, wherein said compound that enhances the activity ofnorepinephrine and/or dopamine is bupropion.
 21. The method of claim 18,wherein said anticonvulsant and said compound that enhances the activityof norepinephrine and/or dopamine are administered separately.
 22. Themethod of claim 18, wherein said anticonvulsant and said compound thatenhances the activity of norepinephrine and/or dopamine are administeredconcurrently.